Chlamydia trachomatis (CT) infections are widespread throughout the World. This bacterial pathogen affects multiple organs including the eye, the respiratory system and the genital and gastrointestinal tracts, producing acute symptomatology and persistent infections that can result in long-term sequelae. If implemented in a timely manner, antibiotic therapy is effective in controlling CT infections. Unfortunately, many cases are asymptomatic, others are treated late, and/or are unsuccessfully managed. Efforts to produce a vaccine against trachoma were initiated decades ago. More recently, with the uncovering of the role of CT in sexually transmitted infections, several laboratories have focused their efforts on producing a vaccine against genital infections. Here, the hypothesis we want to test is that a subunit vaccine formulated with the native major outer membrane protein (nMOMP) of CT can protect non-human primates against an intravaginal (i.vag.) challenge. To initiate these studies, we will first determine the dose of CT serovar F (CT-F) required to infect and induce tubal pathology by inoculating Rhesus Macaques (RM) i.vag. with different doses of CT-F. To facilitate infection the RM will be treated with medroxyprogesterone acetate (MPA) before the i.vag. inoculation with CTF. To establish the level of protection elicited by immunization with live CT, and therefore defining a "gold standard" for the subunit vaccine, the animals will be challenged with the dose of CT-F resulting in infection and tubal pathology in all the animals in the group. To test the ability of a subunit vaccine to protect RM, the animals will be immunized with nMOMP via the intramuscular and subcutaneous (i.m.+s.c.) routes using CpG+Montanide as adjuvants. The RM will be challenged i.vag. and the course of the infection will be followed with cervical cultures. Protection will be determined based on the number of animals with positive cervical cultures and the severity and length of the infection. At autopsy, the genital tract will be evaluated macroscopically and microscopically for the presence of inflammatory reaction, fibrosis, adhesions, strictures, dilatation and hydrosalpinx. Depending on the results obtained with our initial subunit vaccine formulation we will explore alternative antigens, e.g., recombinant MOMP (rMOMP), different routes of immunization, including sublingual and colonic, and mucosal adjuvants, in particular the B subunit of cholera toxin. In conclusion, CT infections are a major health problem in both developed and underdeveloped countries. This proposal will, for the first time, evaluate a subunit vaccine for its ability to protect non-human primates against a CT i.vag. challenge. Decreasing the incidence and prevalence of CT infections with a vaccine would have a major health impact worldwide.